DNA methylation patterns of β-globin cluster in β-thalassemia patients

Reactivation of fetal hemoglobin (HbF, α₂γ₂) holds a therapeutic target for β-thalassemia and sickle cell disease. Although many HbF regulators have been identified, the methylation patterns in β-globin cluster driving the fetal-to-adult hemoglobin switch remains to be determined.

Here, we evaluated DNA methylation patterns of the β-globin cluster from peripheral bloods of 105 β⁰/β⁰ thalassemia patients and 44 normal controls. We also recruited 15 bone marrows and 4 cord blood samples for further evaluation. We identified that the CpG sites in the locus control region (LCR) DNase I hypersensitive site 4 and 3 (HS4-3) regions, and γ- and β-globin promoters displayed hypomethylation in β⁰/β⁰-thalassemia patients, especially for the patients with high HbF level, as compared with normal controls. Furthermore, hypomethylations in most of CpG sites of the HS4-3 core regions were also observed in bone marrows (BM) of β⁰/β⁰-patients compared with normal controls; and methylation level of γ-globin promoter -50 and + 17 CpG sites showed lower methylation level in patients with high HbF level compared with those with low HbF level and a negative correlation with HbF level among β⁰-thalassemia patients. Finally, γ-globin promoter + 17 and + 50 CpG sites also displayed significant hypomethylation in cord blood (CB) tissues compared with BM tissues from normal controls.

Our findings revealed methylation patterns in β-globin cluster associated with β⁰ thalassemia disease and γ-globin expression, contributed to understand the epigenetic modification in β⁰ thalassemia patients and provided candidate targets for the therapies of β-hemoglobinopathies.